Abstract
BackgroundGastric cancer (GC) with hepatic metastasis has a poor prognosis. Understanding the molecular mechanisms involved in hepatic metastasis may contribute to the development of sensitive diagnostic biomarkers and novel therapeutic strategies.MethodsWe performed transcriptome analysis of surgically resected specimens from patients with advanced GC. One of the genes identified as specifically associated with hepatic metastasis was selected for detailed analysis. GC cell lines with knockout of the candidate gene were evaluated in vitro and in vivo. Expression of the candidate gene was analysed in GC tissues from 300 patients.ResultsEthanolamine kinase 2 (ETNK2) was differentially upregulated in GC patients with hepatic metastasis. ETNK2 expression was elevated in GC cell lines derived from haematogenous metastases. ETNK2 knockout significantly suppressed proliferation, invasion, and migration; increased apoptosis; reduced Bcl-2 protein expression; and increased phosphorylated p53 expression. In mouse xenograft models, ETNK2 knockout virtually abolished hepatic metastasis. Stratification of GC patients based on ETNK2 mRNA level revealed significant associations between high ETNK2 tumour expression and both hepatic recurrence and worse prognosis.ConclusionsUpregulation of ETNK2 in GC enhances hepatic metastasis, possibly via dysregulation of p53–Bcl-2-associated apoptosis. ETNK2 expression may serve as a biomarker for predicting hepatic recurrence and a therapeutic target.
Highlights
Gastric cancer (GC) with hepatic metastasis has a poor prognosis
We decided to focus on Ethanolamine kinase 2 (ETNK2) for the following reasons: it showed high specificity for hepatic recurrence indicated by little changes in the peritoneal and nodal recurrence groups, the nucleotide sequence of ETNK2 is available (NM_001297760.2), and there were no previous reports about association between ETNK2 and cancers of the GI tract
In this study, we conducted pattern-specific transcriptome analysis of GC tissues to identify molecules potentially involved in hepatic metastasis
Summary
Gastric cancer (GC) with hepatic metastasis has a poor prognosis. Understanding the molecular mechanisms involved in hepatic metastasis may contribute to the development of sensitive diagnostic biomarkers and novel therapeutic strategies. Stratification of GC patients based on ETNK2 mRNA level revealed significant associations between high ETNK2 tumour expression and both hepatic recurrence and worse prognosis. ETNK2 expression may serve as a biomarker for predicting hepatic recurrence and a therapeutic target. Despite advances in multimodal therapy, recurrence after curative gastrectomy is common, and the 5-year survival rate for patients with advanced GC is 20–40%.2,3. This is due in large part to a combination of frequent diagnosis at an advanced stage, lack of curative therapies, and a paucity of sensitive biomarkers for predicting recurrence. Peritoneal dissemination is more common than hepatic metastasis in GC, despite similar portal vein reflux.[3,5]. Peritoneal dissemination is more common than hepatic metastasis in GC, despite similar portal vein reflux.[3,5] In the past few decades, while the incidence of GC declined steadily especially in diffuse-type GC with a preference for peritoneal dissemination, intestinal-type GC located in junction or cardia with a preference for haematogenous metastasis as represented by hepatic metastasis has been increasing relatively.[6,7]
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